Heparin was introduced to clinical medicine about forty-eight years ago on the basis of experimental work establishing its value in the prevention of venous thrombosis and as an essential aid for successful vascular surgery. For about forty eight years heparin has been used as an essential drug in the diagnosis and treatment of diseases of the heart and blood vessels. It is prepared commercially from beef lung and pork intestinal mucosa. (See Heparin: An Old Drug With A New Paradigm, SCIENCE, November, 1979 Vol. 206 pp. 528-533.)
In 1976, more than nine billion units (six metric tons) of heparin was administered to approximately ten million patients and consumption is believed to have increased yearly since that time. Although heparin is an essential aid for successful vascular surgery, it is not absorbed in the GI tract and thus cannot be administered orally. Accordingly, the drug is generally administered by injection (intravenously or intramuscularly) or subcutaneously.
Strictly speaking heparin is heparinic acid which is a highly sulfated dextrorotatory mucopolysaccharide, having specific anticoagulant properties. Heparinic acid is composed of D-glucosamine and D-glucuronic acid residues. It has a molecular weight which varies from 6,000 to 20,000 depending on the source and method of determination. As used herein, the word heparin will refer to heparinic acid as well as all of the pharmaceutically acceptable salts of heparinic acid. Some of the common salts include calcium salt (calciparine) magnesium salt (magnesium heparinate, cutheparine), potassium salt (clarin) and sodium salt sold under various names including heparin sodium. Sodium salts of heparinic acid are the most commonly used pharmaceutical drug encompassed by the name heparin and such sodium salts make up a white or grayish brown amorphous powder which is odorless and hygroscopic. (See Merck Index, Tenth Edition, Entry No. 4543 which is incorporated herein with respect to its disclosure of heparin and pharmaceutically acceptable salts thereof.)
The most commonly used heparin (heparin sodium) has a potency which is calculated on a dried basis. Its potency is not less than 120 USP heparin units in each mg when derived from lungs and not less than 140 USP heparin units in each mg when derived from other tissues, and not less than 90% and not more than 100% of the potency stated on the label. (See U.S. Pharmacopeia National Formulary 1980 page 365 Vol. XX.)
It was not until 1976, after forty (40) years of using heparin, that researchers realized that it would be possible to deliver heparin via an intrapulmonary route. (See Jaques, et al "Intrapulmonary Heparin, A New Procedure for Anticoagulant Therapy", The Lancet, November 27, 1976 p. 1157-1161.) These researchers utilized a "DeVilbiss ultrasonic nebuliser which contained a volume of 10 to 20 mg heparin per milliliter. In order to administer the heparin, the subjects were instructed to take slow deep breaths for periods of five minutes with rest intervals of one to two minutes for a total time of one and a half hours. The test results of intrapulmonary administration of heparin contrast strikingly with the results obtained with intravenous or subcutaneous heparin in doses of 140 to 150 units per kilogram which produced incoagulability for a short time. With intravenous anticoagulants, prolongation of effect accompanies increased hypocoagulability. After intrapulmonary heparin, the effects last much longer and the hypocoagulability is more moderate. Accordingly, the results obtained utilizing the nebuliser were clearly advantageous. However, in order to obtain these effects the patients were required to inhale heparin from a nebuliser over an extended period of time. Therefore, it could be concluded that although benefits are obtained from the intrapulmonary delivery of heparin, such a delivery means is often too inconvenient for the patient to utilize.
Belgian patent 862,538 discloses the intrapulmonary delivery of heparin wherein sodium heparin is included in an aqueous solution and provided in an aerosol form by means of a nebuliser. The patent specifically discloses the inclusion of an agent for increasing the permeability of heparin through the lung alveoli and bronchial mucosa.
Another study relating to the intrapulmonary delivery of heparin is "Heparin Aerosol - Effect on Blood Coagulation and Pulmonary Function," Hellgren, et al., Thrombosis Research 21; 493-502 Pergamon Press Ltd 1981. A "modified" deVilbiss ultrasonic nebuliser is used for administration which is disclosed as requiring 60-90 minutes. These researchers also recognized that the molecular weight of the heparin administered might have an affect on absorbtion.
Since 1976 researchers have investigated the possibility of intrapulmonary delivery of heparin. However, it appears as though each attempt involves either the use of a nebuliser or direct intratracheal installation. The use of a nebuliser requires a long period of time and is expensive due to the cost of medical personnel required as well as the equipment and the heparin lost by this inefficient means of administration. The use of intratracheal installation generally requires that the patient be anesthetized which increases both the cost and risks involved in administration. Although tests show that heparin may be administered by the intrapulmonary route without toxicity, this means of administration has not been generally accepted because administration by injection is less expensive, safer and more convenient.